Alcohol abuse and alcoholism is a complex disease involving multiple signaling events within the central nervous system. Changes in these signaling pathways as a result of alcohol exposure may lead to neuroadaptations with long-term behavioral consequences such as dependence. Not surprisingly, genetics are a known factor in the development of alcohol abuse, contributing approximately half of the predisposition for abuse. A large amount of research has attempted to identify single genes associated with ethanol abuse, but has shown only moderate success. We propose combining genetic, genomic, and pharmacological tools to study this complex trait. For example, DNA microarrays will allow an unbiased simultaneous examination of changes in gene expression across several thousand genes due to ethanol or divergent genetic backgrounds. This approach has the possibility of identifying genetic and genomic variation contributing to disparities in the molecular adaptations occurring with ethanol exposure. We hypothesize these variations are responsible for regional neurobiological differences controlling ethanol-induced CNS plastic events and subsequent behavioral responses. The proposed study is aimed at understanding the genetic and molecular mechanisms of ethanol-responsive myelin gene networks in the central nervous system as well as their relationship to ethanol behavioral phenotypes. Myelin gene expression is known to be altered by ethanol in both humans and animal models. Pharmacological inhibitors, genetic knockout mice, and microarrays will be used to characterize the molecular mechanisms regulating acute ethanol-responsive myelin gene expression. The overall goal of this study will be accomplished by completing the following specific aims: 1) Determine if Fyn kinase regulates myelin-associated gene expression in mouse prefrontal cortex, 2) Characterize a Fyn kinase 'extended'signaling network involved in acute ethanol- responsive myelin gene expression in mouse prefrontal cortex, and 3) Identify ethanol-related behaviors associated with myelin gene expression and corresponding signaling mechanisms. Investigating the molecular pathways of acute ethanol exposure involved in myelin gene expression may potentially have novel implications in the study of myelin and ethanol-related disorders. PUBLIC HEALTH RELEVANCE: Alcohol abuse and alcoholism significantly affects the health millions of individuals worldwide, however, few effective pharmacotherapies exist to date. Developing newer therapies will require understanding the molecular mechanisms associated with acute and long-term ethanol exposure.